Vaginal dryness is a very common problem which brings physical and emotional distress to many women (Key, E., Nurs. Stand. 5:24-27 (1991)). It most commonly manifests itself during sexual intercourse, which causes dyspareunia and can eventually lead to apareunia. Although it is traditionally considered to be a condition which affects postmenopausal women, it can occur during the premenopausal and perimenopausal years. The use of oral contraceptives may also cause a reduction in vaginal moisture in some women (Reginald, W., et al., Br. J. Obstet. Gynaecol. 96:1148-1152 (1989)). Postpartum vaginal dryness, independent of or as a result of lactation, can be a significant complaint (Wisniewski, P., et al., Am. J. Obstet. Gynecol. 165:1249-1254 (1991)). Women undergoing-chemotherapy or radiotherapy for malignant diseases such as leukemia often experience vaginal dryness as a result of treatment (Cust, M., et al., Br. Med. J. 299: 1494-1497 (1989)). Many disease states, such as systemic sclerosis and other systemic autoimmune disorders (Bhadauria, S., et al., Am. J. Obstet. Gynecol. 172:580-587 (1995)), Ehlers-Danlos syndrome (Sorokin, Y., et al., J. Reprod. Med. 39:281-284 (1994)), diabetes mellitus (Sreebny, L., et al., Diabetes Care 15:900-904 (1992)), and Sjögren's syndrome (Marchesoni, D., et al., Eur. J. Obstet. Gynecol. Reprod. Biol. 63:49-53 (1995)) have decreased vaginal hydration and lubrication problems as significant disease-associated symptoms.
Vulvar pain is defined as the excessive sensitivity of the nerves supplying the mucus membrane of the vulva. This persistent burning and sensitivity in vulvar skin is not caused by identifiable infection. It cannot be cured by surgery. The diseases covered under “vulvar pain” are also referred to as vulvodynia/vulvar vestibulitis, vulvitis, burning vulvar syndrome and is often associated with fibromylagia, irritable bowel syndrome, Sjögren's syndrome, chronic inflammation, and Paget's disease as well as in the absence of any identifiable disease or infection. R. Paul St. Armad, M.D., an endocrinologist at UCLA, has successfully treated fibromylagia with uricosuric (gout) drugs, especially guaifenesin, a drug used to liquefy mucus (Yount, J. J. et al., Women's Health Digest 3(2) 1997). Dr. Armad has found that such gout drugs provide an effective treatment for fibromylagia, even though gout and fibromylagia have no connection. Dr. Armad has found that 24-hour urine samples taken from patients before and after treatment exhibited a significant increase in the excretion of phosphate and a moderate increase of oxalate and calcium after guaifenesin was started. His hypothesis is that an excess of intracellular phosphate, and possibly oxalate, builds up in the cells of fibromylagia sufferers and depresses formation of energy (ATP) in the mitochondria of the cells. It should be noted that the role of ATP in Dr. Armad's theory is as an energy source and not an agonist of the P2Y2 receptor.
Current therapies for increasing vaginal moisture are: lubricating agents such as lubricating creams or jellies, topical estrogen creams, and HRT (hormone replacement therapy). Lubricating jellies provide short-lived and temporary relief, as these are aqueous preparations containing no pharmacologically active agent. Topical estrogen creams, if used on a regular basis, may be absorbed into the systemic circulation. This can cause endometrial stimulation and can lead to endometrial hyperplasia and carcinoma (Whitehead, M., et al., N. Eng. J. Med. 305:1599-1605 (1981)). HRT is effective at relieving symptoms of vaginal atrophy and hence vaginal dryness but has several contraindications and unwanted risks and side effects. A history of gall bladder disease (N. Eng. J. Med., 290:15-19 (1974)) or a personal or family history of reproductive or breast cancer (Harlap, S., Am. J. Obstet. Gynecol. 166:1986-1992 (1992)) are contraindications for estrogen therapy. Other contraindications are: history of stroke, cardiovascular disease, deep-vein thrombosis, superficial thrombophlebitis, liver disease, heavy smoking, high blood pressure, diabetes, uterine bleeding or large fibroids, hyperlipidemia, and gross obesity (Lichtman, R., J. Nurse Midwifery 36:30-48 (1991)). One major disadvantage of HRT is the resumption of monthly withdrawal bleeds, which many postmenopausal women will not accept. Some women, even while on HRT, still experience a degree of vaginal dryness (Key, E., Nurs. Stand. 5:24-27 (1991)).
It has been shown that uridine 5′-triphosphate (UTP) and dinucleotides such as diuridine tetraphosphate are potent agonists of P2Y2 purinergic receptors found on the surface of human airway epithelium. UTP has been shown to increase both the rate and total amount of mucin secreted by goblet cells in vitro (Lethem, M., et al., Am. J. Respir. Cell Mol. Biol. 9:315-322 (1993)). UTP has also been shown to increase-chloride secretion, and hence, water secretion from airway epithelial cells in vitro (Mason, S., et al., Br. J. Pharmacol. 103:1649-1656 (1991)).
Thus, as a result of the ineffectiveness and risks of current therapies, medical researchers have sought to develop alternatives for the treatment of vaginal dryness. Because of the demonstrated ability of UTP and dinucleotides, such as diuridine tetraphosphate, to increase hydration of airway epithelial secretions and stimulate release of mucins, applicants were motivated to investigate whether UTP and other P2Y2 and/or P2Y4 purinergic receptor agonists could stimulate hydration and mucin production in the vaginal and cervical epithelia.